Glycogen mechanism

FIGURE 15.17 The mechanism of covalent modification and allosteric regnlation of glycogen phosphorylase. The T states are bine and the R states bine-green. 

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

The principal enzymes controlling glycogen metabolism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and... 

Figure 18-3. The biosynthesis of glycogen. The mechanism of branching as revealed by adding "C-labeled glucose to the diet in the living animal and examining the liver glycogen at further intervals.

Villar-Palasi C On the mechanism of inactivation of muscle glycogen phosphorylase by insulin. Biochim Biophys Acta 1994 1224 384. 

Hormones and neuronal activity affect brain glycogen metabolism. Glycogen is affected by hormones endogenous to the brain including vasoactive intestinal peptide and noradrenaline, as well as circulating hormones, such as insulin [61, 63, 64]. The mechanism whereby insulin exerts an effect on glycogen metabolism in brain has not been determined [63]. Glycogen metabolism in brain, unlike in other tissues, is controlled locally, due to differential local metabolic rates. 

Di-tt-octylphthalate has been shown to be a mild liver toxin at high doses in acute- and intermediate-duration studies in rodents. While the mechanism of action for these hepatic effects is not known, di-w-octylphthalate does not appear to behave like other phthalate esters such as di(2-ethylhexyl)phthalate, which have been shown to be hypolipidemic peroxisome proliferators. Instead, the liver changes associated with exposure to di- -octylphthalate are characterized by marked centrilobular accumulation of fat and loss of glycogen, accompanied by reduced glucose-6-phosphatase activity and some centrilobular necrosis. 

There were also less concrete considerations. In the early 1950s glycogenolysis was still believed to be completely reversible. UTP dependency and the glycogen synthase reactions had not yet been discovered nor had phosphofructokinase been shown to act irreversibly. The mechanism of protein synthesis was still a mystery. Laboratories studying proteolysis had shown that the peptide bond could be resynthesized by peptidases, although under very restricted conditions. Reversibility seemed to be an accepted property of the major metabolic pathways. 

This sort of control is usually achieved by either covalent modification (phosphorylation or de phosphorylation as in glycogen metabolism) or by proteolytic cleavage (e.g. activation of digestive enzymes in the gut, or blood clotting mechanism. 

As is often the case, tissue-specific control mechanisms operate to optimise adaptation to particular conditions. For example, muscle contraction requires an increase in cytosolic calcium ion concentration (see Section 7.2.1, Figure 7.4). During exercise when energy generation needs to be increased, or from a more accurate metabolic point of view, when the ATP-to-ADP ratio falls rapidly, and the accompanying rise in [Ca2 + ] activate (i) glycogen phosphorylase which initates catabolism of... 

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